Open access
Stroke Vasc Neurol: first published as 10.1136/svn-2021-001166 on 7 April 2022. Downloaded from http://svn.bmj.com/ on August 8, 2023 at Instituto Mexicano del Seguro Social (IMSS).
To cite: Shah J, Liu S, Yu W.
Contemporary antiplatelet
therapy for secondary stroke
prevention: a narrative review of
current literature and guidelines.
Stroke & Vascular Neurology
2022;7: e001166. doi:10.1136/
svn-2021-001166
Received 8 June 2021
Accepted 16 February 2022
Published Online First
7 April 2022
© Author(s) (or their
employer(s)) 2022. Re-­use
permitted under CC BY-­NC. No
commercial re-­use. See rights
and permissions. Published by
BMJ.
1
Neurology, University of
California, Irvine, California, USA
2
Neurology, Tiantan Hospital,
Beijing, China
Correspondence to
Dr Wengui Yu; w
​ yu@​uci.​edu
406
Contemporary antiplatelet therapy for
secondary stroke prevention: a narrative
review of current literature
and guidelines
Jay Shah,1 Shimeng Liu ‍ ‍,1,2 Wengui Yu ‍ ‍1
ABSTRACT
Antiplatelet therapy is one of the mainstays for secondary
stroke prevention. This narrative review aimed to highlight
the current evidence and recommendations of antiplatelet
therapy for stroke prevention.
We conducted advanced literature search for antiplatelet
therapy. Landmark studies and randomised controlled
trials evaluating antiplatelet therapy for secondary stroke
prevention are reviewed. Results from Cochrane systematic
review, pooled data analysis and meta-­analysis are
discussed.
Single-­antiplatelet therapy (SAPT) with aspirin, aspirin/
extended-­release dipyridamole or clopidogrel reduces the
risk of recurrent ischaemic stroke in patients with non-­
cardioembolic ischaemic stroke or transient ischaemic
attack (TIA). Dual-­antiplatelet therapy (DAPT) with
aspirin and clopidogrel or ticagrelor for 21–30 days is
more effective than SAPT in patients with minor acute
noncardioembolic ischaemic stroke or high-­risk TIA.
Prolonged use of DAPT is associated with higher risk
of haemorrhage without reduction in stroke recurrence
than SAPT. Compared with placebo, aspirin reduces the
relative risk of recurrent stroke by approximately 22%.
Aspirin/dipyridamole and cilostazol are superior to aspirin
but associated with significant side effects. Cilostazol
or ticagrelor might be more effective than aspirin or
clopidogrel in patients with intracranial stenosis.
SAPT is indicated for secondary stroke prevention in
patients with non-­cardioembolic ischaemic stroke or
TIA. DAPT with aspirin and clopidogrel or ticagrelor for
21–30 days followed by SAPT is recommended for patients
with minor acute noncardioembolic stroke or high-­risk TIA.
Selection of appropriate antiplatelet therapy should also be
based on compliance, drug tolerance or resistance.
INTRODUCTION
Stroke is the second-­leading cause of death
and the third-­leading cause of death and disa-
bility combined in 2019 globally.1 Platelets are
activated by collagen, ADP and arachnoid acid
metabolite thromboxane A2. Activated plate-
lets induce platelet aggregation and blood
clot formation, resulting in acute ischaemic
stroke (AIS) or transient ischaemic attack
(TIA). Antiplatelet agents inhibit platelet
aggregation and reduce the risk of AIS or
TIA.2 Aspirin, clopidogrel, dipyridamole/
Shah J, et al. Stroke & Vascular Neurology 2022;7:e001166. doi:10.1136/svn-2021-001166
Review
aspirin, cilostazol and ticagrelor are
commonly used antiplatelet agents. In recent
years, numerous randomised controlled
trials (RCTs), Cochrane systematic reviews
and meta-­analyses evaluated the efficacy and
safety of antiplatelet therapy for secondary
stroke prevention.3–9 Due to the complexity
of stroke aetiology and diverse mechanisms
of antiplatelet agents (figure 1), it is essential
to select optimal antiplatelet therapy in the
real-­world practice. In this narrative review,
we aimed to highlight current evidence and
Protected by copyright.
recommendations of the antiplatelet therapy
for secondary stroke prevention.2–10
METHODS AND MATERIALS
We conducted a literature search of peer-­
reviewed English language articles in PubMed
and Cochrane Library using the following
keywords: antiplatelet therapy AND stroke,
antiplatelet therapy AND ischaemic stroke,
antiplatelet therapy AND transient ischaemic
attack, antiplatelet agent AND stroke, anti-
platelet agent AND ischaemic stroke, anti-
platelet agent AND transient ischaemic
attack. The search was performed for studies
published between 1 January 1980 and 15
November 2021. Landmark studies, RCTs,
Cochrane systematic review, pooled data
analysis and meta-­analysis were included for
discussion.
RESULTS
Single-antiplatelet therapy
Aspirin
Aspirin irreversibly inactivates cyclooxygenase
1 (COX1) and inhibits platelet aggregation.
In 1994, the Antiplatelet Trialists’ Collabo-
ration study evaluated 145 RCTs regarding
aspirin in preventing ischaemic stroke,
myocardial infarct or vascular death.11 Aspirin
treatment was associated with a 22% relative

Figure 1 The mechanisms of antiplatelet agents. Aspirin
irreversibly inhibits cyclooxygenase 1 (COX1) activity.
Clopidogrel and ticagrelor blocks ADP receptor. Dipyridamole
and cilostazol inhibits phosphodiesterase, thereby
increasing cAMP levels and preventing platelet activation.
ADP, adenosine diphosphate; COX, cyclooxygenase; GP,
glycoprotein; TXA2, thromboxane A2.
risk reduction of vascular event in patients with history of
AIS or TIA.
Table 1 lists the key RCTs of antiplatelet agents for
stroke prevention. The International Stroke Trial (IST)
randomised patients to aspirin 300 mg daily, subcuta-
neous heparin, both or neither within 48 hours of isch-
aemic stroke for up to 2 weeks.12 The aspirin group had
significantly fewer recurrent ischaemic stroke (2.8% vs
3.9%, p<0.001) but equal rates of haemorrhage. The
Chinese Acute Stroke Trial was similar in design except
for a different aspirin dose (160 mg daily) and duration
(4 weeks).13 There were significantly lower absolute risk
of recurrent ischaemic stroke in the aspirin group (1.6%
vs 2.1%, p=0.01). In a Cochrane systematic review of 8
RCTs with 41 483 participants on oral antiplatelet therapy
for stroke prevention, aspirin 160–300 mg daily, started
within 48 hours of stroke onset, reduced the risk of early
recurrent ischaemic stroke without significant risk of
haemorrhagic complications.5
Dipyridamole and aspirin/dipyridamole
Dipyridamole inhibits phosphodiesterase and platelet
activation.14 European Stroke Prevention Study (ESPS)
randomised patients with either stroke or TIA within 3
months to receive aspirin/dipyridamole (325 mg/75 mg)
or placebo three times a day.15 The treatment group was
associated with 33% relative risk reduction in stroke and
death. ESPS-­2 randomised patients with TIA or ischaemic
stroke within 3 months to either aspirin 25 mg two times
a day, dipyridamole 200 mg two times a day, aspirin/
dipyridamole or placebo.16 Compared with placebo, rela-
tive stroke risk was significantly reduced by 18%, 16%
and 37%, respectively, suggesting a synergistic effect from
combination therapy.
There was no significant difference in risk of bleeding
between aspirin and combination therapy group.
 J, et al. Stroke & Vascular Neurology 2022;7:e001166. doi:10.1136/svn-2021-001166
Shah
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Stroke Vasc Neurol: first published as 10.1136/svn-2021-001166 on 7 April 2022. Downloaded from http://svn.bmj.com/ on August 8, 2023 at Instituto Mexicano del Seguro Social (IMSS).
The main side effects of dipyridamole were headache
and diarrhoea.
European Stroke Prevention in Reversible Ischaemia
Trial randomised patients with TIA or minor stroke within
6 months to either aspirin/dipyridamole or aspirin.17 The
dose of aspirin ranged from 30 to 325 mg, with majority
receiving 30 mg daily. Aspirin/dipyridamole therapy was
associated with an absolute risk reduction of 1% per year,
corresponding to a number needed to treat of 104 to
prevent 1 stroke, death or myocardial infarction. Of note,
34% of patients discontinued aspirin/dipyridamole due
to side effects, mostly headache.
The Prevention Regimen for Effectively Avoiding
Second Strokes trial randomised patients to either
aspirin/dipyridamole or clopidogrel.18 At a mean 2.5 years
follow-­up, there was no significant difference in recurrent
stroke (9% vs 8.8%) between the two groups.
Aspirin/dipyridamole has been rarely used due to high
cost and significant side effect.
Cilostazol
Cilostazol also inhibits phosphodiesterase and platelet
aggregation.19 CSPS randomised patients with recent
stroke to cilostazol 100 mg two times daily or placebo.19
Cilostazol was associated with a relative stroke risk reduc-
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tion by 41.7% (p=0.015). In CSPS-­2 trial,20 2757 patients
were randomised to receive cilostazol 100 mg two times
daily (n=1379) or aspirin 81 mg daily (n=1378). At mean
29-­month follow-­up, cilostazol group had a 34% relative
risk reduction in cerebral infarction than aspirin group
(2.76% vs 3.71%, p=0.0357) and lower haemorrhagic
events (0.77% vs 1.78%; p=0.0004).
​CSPS.​com (CSPS for antiplatelet Combination) eval-
uated the efficacy of cilostazol and either aspirin or
clopidogrel versus either aspirin or clopidogrel mono-
therapy.21 Patients with ischaemic stroke within the
previous 6 months were eligible for enrolment if at least
two vascular risk factors were present and at least 50%
stenosis of either an extracranial or intracranial artery.
Dual-­antiplatelet therapy (DAPT) was found to be supe-
rior to single-­antiplatelet therapy (SAPT) in annual rate
of ischaemic stroke (2.2% vs 4.5%, p=0.001). There was
no significant difference in life-­ threatening bleeding
between the two group. In a systemic review and meta-­
analysis of RCTs,22 cilostazol was shown to have lower rates
of recurrent ischaemic stroke, haemorrhages or deaths,
but higher rates of headache, palpitations and discontin-
uation than placebo, aspirin or clopidogrel.
Of note, essentially all clinical trials on cilostazol were
conducted in Asia and results have not been replicated in
other ethnic populations.22
Ticlopidine
Ticlopidine was the first developed ADP receptor (P2Y12)
antagonist.23 However, due to serious adverse effects,
including hepatotoxicity and bone marrow suppression,
it is not used in clinical practice.
407
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Stroke Vasc Neurol: first published as 10.1136/svn-2021-001166 on 7 April 2022. Downloaded from http://svn.bmj.com/ on August 8, 2023 at Instituto Mexicano del Seguro Social (IMSS).
Table 1 Landmark randomised controlled trials evaluating antiplatelet therapy in secondary stroke prevention
Study Study population Trial design Mean follow-­up Outcomes

IST 19 435 patients with Randomised to aspirin 6 months Rate of dependence at 6 months (aspirin vs no
(1997)12 AIS within 48 hours of 300 mg daily, subcutaneous aspirin): 62.2% vs 63.5%, p=0.07.
symptom onset in 36 heparin, both or neither for Ischaemic stroke at 14 days (aspirin vs no
countries up to 14 days. aspirin): 2.8% vs 3.9%, p<0.001.
CAST 21 106 patients with AIS Aspirin 160 mg vs placebo for 4 weeks Mortality (aspirin vs placebo): 3.3% vs 3.9%,
(1997)13 were treated within 48 up to 4 weeks p=0.04.
hours of symptom onset Recurrent ischaemic stroke (aspirin vs placebo):
in China 1.6% vs 2.1%, p=0.01.
ESPS 2500 patients with recent Dipyridamole 75 mg plus 2 years Stroke and death (dipyridamole/aspirin vs
(1987)15 ischaemic stroke or TIA in aspirin 325 mg or placebo placebo): 33% relative risk reduction (p<0.01).
Europe three times daily
ESPS-­2 (1996)16 6600 patients with prior Aspirin 25 mg two times daily, 2 years Relative stroke risk reduction compared with
stroke or TIA within 3 dipyridamole 200 mg two placebo: aspirin 18% (p=0.013), dipyridamole
months in Europe times daily, dipyridamole/ 16% (p=0.039), combination 37% (p ‍ ‍ 0.001)
aspirin or placebo
ESPRIT (2006)17 2739 patients with TIA/ Aspirin 30–325 mg daily plus 3.5 years The composite of death from all vascular causes,
minor stroke within 6 dipyridamole 200 mg two non-­fatal stroke, non-­fatal myocardial infarction
months times daily vs aspirin or major bleeding complication
(Aspirin/dipyridamole vs aspirin): 12.7% vs
15.7%, HR: 0.80, 95% CI 0.66 to 0.98.
PRoFESS (2008)18 20 332 patients with Aspirin/dipyridamole 2.5 years First recurrence of stroke (aspirin/dipyridamole
ischaemic stroke within (25/200 mg) two times daily vs clopidogrel): 9.0% vs 8.8%; p=NS.
90 days of randomisation vs clopidogrel 75 mg daily Risk of major haemorrhage: 4.1% vs 3.6%,
and an age of 50 years p=NS.
or older.
CSPS 1095 with ischaemic Cilostazol 100 mg two times 1.5 years Ischaemic stroke relative risk reduction
(2000)19 stroke within 1–6 months daily vs placebo (cilostazol vs placebo): 41.7% (95% CI 9.2% to

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in Japan 62.5%; p=0.015)
CSPS-­2 (2010)20 2757 patients with a Cilostazol 100 mg two times 29 months Recurrence of cerebral infarction (cilostazol vs
cerebral infarction within daily vs aspirin 81 mg aspirin): 2.76% vs 3.71%, p=0.0357.
previous 26 weeks in Haemorrhage: 0.77% vs 1.78; p=0.0004.
Japan
CSPS.com 1879 patients with Aspirin 81 mg or clopidogrel 1.4 years Annual rate of recurrent stroke (DAPT vs SAPT):
(2019)21 recent ischaemic stroke 75 mg and cilostazol 100 mg 2.2% vs 4.5%, HR 0.49 (95% CI 0.31 to 0.76;
and either at least 50% two times daily vs aspirin or p=0.001)
stenosis or more than two clopidogrel
vascular risk factors
CAPRIE (1996)24 19 185 patients with either Clopidogrel 75 mg vs aspirin 1.9 years Annual rate of ischaemic stroke, myocardial
recent ischaemic stroke 325 mg daily infarction or cardiovascular death (Clopidogrel vs
or myocardial infarction aspirin): 5.32% vs 5.83%, p=0.043.
SOCRATES 13 199 patients with Ticagrelor 90 mg two times 4 months Rate of recurrent stroke, myocardial infarction
(2016)25 recent stroke or high-­risk daily vs aspirin 100 mg daily or death (Ticagrelor vs aspirin): 6.7% vs 7.5%,
TIA within previous 24 p=0.07.
hours Rate of ischaemic stroke: 5.8% vs 6.7%;
p=0.046.

AIS, acute ischaemic stroke; CAPRIE, Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events; CAST, Chinese Acute Stroke Trial; CSPS, Cilostazol stroke
prevention study ; DAPT, dual-­antiplatelet therapy; ESPRIT, European Stroke Prevention in Reversible Ischaemia Trial; ESPS, European Stroke Prevention Study
2; IST, International Stroke Trial; NS, not significant; PRoFESS, Prevention Regimen for Effectively Avoiding Second Strokes; SAPT, single-­antiplatelet therapy;
SOCRATES, Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes; TIA, transient ischaemic attack.

Clopidogrel Therefore, clopidogrel is considered a good option for

Clopidogrel is a thienopyridine that blocks ADP receptor
P2Y12 and interferes with platelet cross-­linking and aggre-
gation.23 The Clopidogrel vs Aspirin in Patients at Risk of
Ischaemic Events trial randomised patients with stroke,
myocardial infarction or peripheral vascular disease to
either aspirin 325 mg or clopidogrel 75 mg daily.24 The
clopidogrel group had a significantly lower annual rate
of vascular event than the aspirin group (5.32% vs 5.83%,
p=0.043). Of note, the relative risk reduction in patients
with prior stroke was 7.3% and not statistically significant.
Haemorrhage risks were similar between the two groups.
secondary stroke prevention.
Ticagrelor
Ticagrelor is a new generation P2Y12 receptor antagonist.
It is not dependent on hepatic activation and has a more
potent antiplatelet effect.25 The Acute Stroke or Tran-
sient Ischaemic Attack Treated with Aspirin or Ticagrelor
and Patient Outcomes trial randomised patients with
minor stroke (National Institutes of Health Stroke Scale
(NIHSS) score <5) or high-­risk TIA within 24 hours to
either ticagrelor 90 mg two times a day or aspirin 100 mg

408 Shah J, et al. Stroke & Vascular Neurology 2022;7:e001166. doi:10.1136/svn-2021-001166


daily for 90 days.25 There was no significant difference in
the rate of stroke, myocardial infarction or death between
the two groups (6.7% vs 7.5%; HR 0.89; p=0.07). Haem-
orrhage risk was also similar. Of note, ticagrelor had a
17.5% discontinuation rate primarily due to dyspnoea
and bleeding. A subgroup analysis showed that ticagrelor
was superior to aspirin in patients with ipsilateral athero-
sclerotic stenosis.26
Glycoprotein IIb/IIIa antagonists
Glycoprotein IIb/IIIa receptor antagonists, including
abciximab, eptifibatide and tirofiban, represent a unique
class of antiplatelet agents. Abciximab is a chimeric
mouse/human monoclonal antibody with high affinity
for the platelet glycoprotein IIb/IIIa receptor.27 It was
used as an adjunct to thrombolysis or endovascular proce-
dures. Abciximab in Emergency Treatment of Stroke Trial
evaluated the efficacy and safety of abciximab in patients
with AIS within 5 hours of symptoms onset. It was termi-
nated early after 808 enrolments due to an unfavourable
benefit–risk profile.28 There was significantly higher rate
of symptomatic or fatal intracranial haemorrhage in the
abciximab group (5.5% vs 0.5%; p=0.002) without signifi-
cant outcome benefit (32% vs 33%; p=0.944). Therefore,
glycoprotein IIb/IIIa antagonists for patients with AIS is
harmful and should not be used for stroke prevention.10
Dual-antiplatelet therapy
The key RCTs investigating the efficacy of DAPT in
secondary stroke prevention are listed in table 2. Manage-
ment of Atherosclerosis with Clopidogrel in High-­Risk
Patients trial randomised patients with recent ischaemic
stroke or TIA to either clopidogrel 75 mg or aspirin 75 mg
and clopidogrel 75 mg daily for 18 months.29 There was a
non-­significant difference in primary outcomes (15.7% vs
16.7%) but a significantly higher risk of life-­threatening
bleeding in the DAPT group (2.6% vs 1.3%).
Subsequently, Clopidogrel for High Atherothrom-
botic Risk and Ischaemic Stabilisation, Management and
Avoidance and SPS3 (Stoke Prevention of Small Subcor-
tical Strokes) showed no difference in stroke recurrence
but higher risk of bleeding in the DAPT group in patients
with atherosclerotic risk factors or lacunar stroke, respec-
tively.30 31
Clopidogrel in High-­Risk Patients with Acute Nondis-
abling Cerebrovascular Events (CHANCE) evaluated
DAPT for 21 days in Chinese population with high-­risk
TIA or minor ischaemic stroke within 24 hours of symptom
onset.32 A total of 5170 patients were randomised to
either clopidogrel (300 mg on day 1, followed by 75 mg
daily) for 90 days plus aspirin 75 mg daily for the first 21
days or placebo plus aspirin 75 mg daily for 90 days. DAPT
group had a significantly lower rate of ischaemic or haem-
orrhagic stroke at 90 days than aspirin group (8.2% vs
11.7%, HR 0.68; p<0.001). The absolute risk reduction
was 3.5%. There was no significant difference in the rate
of haemorrhage between the two groups. The benefit
persisted during 1-­year follow-­up.33
 J, et al. Stroke & Vascular Neurology 2022;7:e001166. doi:10.1136/svn-2021-001166
Shah
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Stroke Vasc Neurol: first published as 10.1136/svn-2021-001166 on 7 April 2022. Downloaded from http://svn.bmj.com/ on August 8, 2023 at Instituto Mexicano del Seguro Social (IMSS).
To determine if the results transcend to a broader
population, POINT (Platelet-­Oriented Inhibition in New
TIA and Minor Ischaemic Stroke) trial was conducted in
North America, Europe, Australia and New Zealand.34
It showed a significant risk reduction in recurrent isch-
aemic events (5.0% vs 6.5%, p=0.02 but increased rate
of bleeding (0.9% vs 0.4%, p=0.02) with DAPT. Of note,
there were some differences in the study design between
POINT and CHANCE. The POINT trial included a
higher loading dose of clopidogrel (600 mg) and longer
DAPT duration (90 days). These differences may explain
the increased risk of bleeding in the POINT trial.
The (Acute Stroke or Transient Ischaemic Attack
Treated with Ticagrelor and ASA for Prevention of
Stroke and Death) trial randomised patients with a mild-­
to-­
moderate acute noncardioembolic ischaemic stroke
(NIHSS score ≤5) or TIA within 24 hours of symptom
onset to either ticagrelor plus aspirin or placebo plus
aspirin for 30 days.35 There were significant lower rates
of stroke or death (5.5% vs 6.6%, HR, 0.83; 95% CI 0.71
to 0.96; p=0.02) and ischaemic stroke (5.0% vs 6.3%, HR,
0.79; 95% CI, 0.68 to 0.93; p=0.004), but higher rate of
severe bleeding (0.5% vs 0.1%, p=0.001) in the DAPT
group. Exploratory analysis showed that ticagrelor plus
aspirin was associated with lower rate of disabling stroke
or death than aspirin alone (4.0% vs 4.7%, p=0.001).36
Protected by copyright.
For every 1000 patients, DAPT would prevent 11 strokes
or deaths at the cost of four severe haemorrhages. The
number needed to treat to benefit one patient is 143. In
subgroup analysis of patients with ipsilateral atheroscle-
rotic stenosis, ticagrelor plus aspirin was associated with
lower rate of stroke or death than aspirin alone (8.1% vs
10.9%, p=0.023), resulting in a number needed to treat of
34 (95% CI 19 to 171).37
Stenting vs Aggressive Medical Management for
Preventing Recurrent Stroke in Intracranial Stenosis
(SAMMPRIS) trial compared medical therapy with
intracranial stenting.38 Patients with a TIA or stroke
attributed to 70%–99% stenosis of an intracranial artery
were randomised to aggressive medical management
with aspirin 325 mg and clopidogrel 75 mg daily for
3 months vs angioplasty and stenting plus aggressive
medical management. The study was stopped early after
enrolment of 450 patients due to a higher 30-­day rate of
stroke and death in the stenting group (14.7% vs 5.8%,
p=0.002) primarily due to periprocedural complica-
tions. At a median follow-­up of 32.4 months, the risk of
stroke or death was 23% in the stenting group vs 15%
in the medical group.39 These results supported the use
of DAPT for 90 days in patients with symptomatic high-­
grade intracranial stenosis.10
CHANCE-­2 trial randomised 6412 patients with a minor
ischaemic stroke or TIA and CYP2C19 loss-­of-­function
alleles to aspirin for 21 days plus ticagrelor or clopidogrel
for 90 days.40 The risk of new stroke at 90 days was modestly
lower in ticagrelor group (6.0% vs 7.6%, p=0.008). There
was no difference in rate of severe or moderate bleeding
between the two groups (0.3% vs 0.3%), but ticagrelor
409
Open access
Table 2 Randomised controlled trials evaluating dual-­antiplatelet therapy (DAPT) in secondary stroke prevention
Study Study population
29
MATCH (2004) 7599 patients with ischaemic Aspirin 75 mg daily plus
stroke or TIA within 3 months clopidogrel 75 mg daily or
placebo plus clopidogrel 75 mg
daily
CHARISMA 15 603 patients with
(2006)30 cerebrovascular disease or
multiple risk factors
SPS3 (2012)31 3020 patients with lacunar
infarcts within 180 days
(n=3020)
CHANCE (2013)32 5170 patients with minor
ischaemic stroke or high-­
risk TIA within 24 hours of
symptom onset in China.
POINT (2018)34 4881 patients with minor
ischaemic stroke or TIA within followed by 75 mg daily for 90
12 hours
THALES (2020)35 11 016 patients with mild-­
to-­moderate acute non-­
cardioembolic ischaemic
stroke, with an NIHSS
score ≤5 or TIA within 24
hours after symptoms onset
SAMMPRIS 451 patients with stroke
(2011)38 39 within 30 days due to 70%–
99% stenosis of intracranial
artery
CHANCE-­2 6412 patients with a minor
(2021)40 ischaemic stroke or TIA and
CYP2C19 loss-­of-­function
alleles within 24 hours of
symptom onset.
410
Trial design
18 months
Aspirin 75–162 mg daily plus
clopidogrel 75 mg daily or
aspirin 75–162 mg daily plus
placebo
Aspirin 325 mg daily plus
clopidogrel 75 mg daily or
aspirin 325 mg daily plus
placebo
Clopidogrel 300 mg on day 1
followed by 75 mg daily for 90
days, plus aspirin 75 mg daily
for 21 days or placebo plus
aspirin 75 mg daily for 90 days.
Clopidogrel 600 mg loading
days plus aspirin 50–325 mg
daily or placebo plus aspirin
daily for 90 days
Ticagrelor 180 mg loading
dose followed by 90 mg two
times daily plus aspirin 300–
325 mg on day 1 followed by
75–100 mg daily or matching
placebo plus aspirin.
Aspirin 325 mg daily plus
clopidogrel 75 mg daily or
stenting plus aspirin and
clopidogrel
Ticagrelor 180 mg on day 1
followed by 90 mg two times
daily or Clopidogrel 300 mg on
day 1 followed by 75 mg daily.
Both groups received aspirin
75 mg daily for 21 days.
Shah J, et al. Stroke & Vascular Neurology 2022;7:e001166. doi:10.1136/svn-2021-001166
Stroke Vasc Neurol: first published as 10.1136/svn-2021-001166 on 7 April 2022. Downloaded from http://svn.bmj.com/ on August 8, 2023 at Instituto Mexicano del Seguro Social (IMSS).
Mean follow-­up Outcomes
Rate of primary endpoints
(aspirin plus clopidogrel vs
clopidogrel): 15.7% vs 16.7%,
p=0.244.
Rate of life-­threatening
bleeding: 2.6% vs 1.3%,
p<0.0001
2.3 years Rate of stroke, myocardial
infarction or death Aspirin plus
clopidogrel vs aspirin): 6.8% vs
7.3%, p=0.22
Rate of stroke 1.9% vs 2.4%,
p=0.03
Rate of moderate bleeding:
2.1% vs 1.3, p<0.001
3.4 years Rate of primary outcome of
ischaemic or haemorrhagic
stroke: 2.5% (dual) vs 2.7%
(aspirin), HR 0.92, 95% CI 0.72
to 1.16, p=0.48
90 days Ischaemic or haemorrhagic
stroke (Clopidogrel plus aspirin
vs aspirin): 8.2% vs 11.7%; HR
0.68, 95% CI 0.57 to 0.81, p‍ ‍
0.001.
Protected by copyright.
Severe or moderate bleeding:
0.3% vs 0.3%.
90 days Primary outcome of recurrent
stroke, death, myocardial
infarction (Clopidogrel plus
aspirin vs aspirin):
5.0% (dual) vs 6.5% (aspirin),
p=0.02
Risks of major haemorrhage:
0.9% (dual) vs 0.4% (aspirin),
p=0.02
30 days Primary outcome of stroke or
death (Ticagrelor plus aspirin vs
aspirin): 5.5% vs 6.6%, p=0.02.
Ischaemic stroke: 5.0% vs
6.3%, p=0.004.
Incidence of disability: no
difference
Severe bleeding: 0.5% vs 0.1%,
p=0.001.
90 days Rate of stroke or death within
30 days (DAPT vs stenting
plus DAPT): 5.8% vs 14.7%;
p=0.002.
Ischaemic stroke or death
at year 3: 14.9% vs 23.9%,
p=0.0193.
90 days New stroke (Ticagrelor plus
aspirin vs clopidogrel plus
aspirin): 6.0% vs 7.6%; HR
0.77, 95% CI 0.64 to 0.94,
p=0.008.
Severe or moderate bleeding:
0.3% vs 0.3%.
Continued
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Stroke Vasc Neurol: first published as 10.1136/svn-2021-001166 on 7 April 2022. Downloaded from http://svn.bmj.com/ on August 8, 2023 at Instituto Mexicano del Seguro Social (IMSS).
Table 2 Continued
Study Study population Trial design Mean follow-­up Outcomes
41
TARDIS (2018) 3096 patients with ischaemic Aspirin (300 mg load, 75 mg 90 days The incidence of recurrent
stroke or TIA within 48 hours daily)+clopidogrel (300 mg load, stroke or TIA (Triple therapy vs
after symptom onset 75 mg daily)+dipyridamole clopidogrel or Aggrenox):
200 mg two times daily vs either 6% vs 7%; adjusted OR 0.90,
clopidogrel alone or combined 95% CI 0.67 to 1.20, p=0.47.
aspirin and dipyridamole). Severe bleeding: 3% vs 1%;
adjusted OR 2.54, 95% CI 2.05
to 3.16, p<0·0001.

CHANCE-­2, Clopidogrel in High-­Risk Patients with Acute Nondisabling Cerebrovascular Events; CHARISMA, Clopidogrel for High
Atherothrombotic Risk and Ischaemic Stabilisation, Management and Avoidance; MATCH, Management of Atherosclerosis with
Clopidogrel in High-­Risk Patients; NIHSS, National Institutes of Health Stroke Scale; POINT, Platelet-­Oriented Inhibition in New TIA;
SAMMPRIS, Stenting vs Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis; THALES, Transient
Ischaemic Attack Treated with Ticagrelor and ASA for Prevention of Stroke; TIA, transient ischaemic attack; TRADIS, Therapy with
Dipyridamole in Patients with Acute Cerebral Ischaemia.

was associated with more total bleeding events (5.3% vs
2.5%).
The Antiplatelet Therapy with Aspirin, Clopidogrel
and Dipyridamole vs Clopidogrel Alone or Aspirin-­
Dipyridamole in Patients with Acute Cerebral Ischaemia
trial compared triple antiplatelet therapy versus SAPT.41
After randomising 3096 patients within 48 hours of AIS
or TIA, the trial was stopped early due to significantly
Antiplatelet resistance
One-­ third of patients who had a stroke may develop
recurrent stroke while on antiplatelet therapy, partly due
to aspirin or clopidogrel resistance.43–45 In the laboratory
studies, aspirin resistance is defined as a failure to achieve
reduction in TXA2 formation.44 Clopidogrel resistance
refers to the inability to inhibit ADP-­mediated platelet
aggregation.45

more bleeding in the triple therapy group (20% vs 9%,
p<0.001) without a decrease in recurrent stroke or TIA
within 90 days (6% vs 7%, p=0.47). Therefore, triple anti-
platelet therapy is harmful and should not be used for
stroke prevention.10 41
Cochrane systematic review, pooled data analysis and
meta-­ analysis of RCTs demonstrated that DAPT with
aspirin and clopidogrel or ticagrelor for 21–30 days is
more effective than SAPT for secondary stroke preven-
tion when initiated early after the onset of minor stroke or
high-­risk TIA.3 6–9 However, when initiated later and used
longer than 90 days, DAPT increases the risk of bleeding
without reduction of stroke recurrence than SAPT.7–9
Recommendations
The current evidence-­based recommendations on anti-
platelet therapy for secondary stroke prevention are
summarised in table 3.3–10
Special considerations
Antiplatelet therapy after intracerebral haemorrhage
Restart or Stop Antithrombotics Randomised Trial
(RESTART) compared starting vs avoiding antiplatelet
agent after intracerebral haemorrhage (ICH).42 At a
median 3-­year follow-­up of 537 participants, there was
no significant difference in recurrent ICH (8.2% vs
9.3%, p=0.64) or major vascular events (26.8% vs 32.5%,
p=0.14) between two group.
Restarting antiplatelet therapy after ICH should be
considered, particularly in patients with high-­risk throm-
boembolic conditions.
Protected by copyright.
The most common cause of inadequate antiplatelet
therapy is non-­ compliance.46 47 Approximately 50% of
patients either stop taking medication or fail to adhere to
the prescribed dose at 1 year.
Potential drug interactions may also result in reduced
effect of antiplatelet therapy. Concomitant use of NSAIDs,
particularly ibuprofen, offsets the clinical benefit of
aspirin.48 Proton-­pump inhibitors (PPIs) inactivates the
hepatic enzyme that converts clopidogrel to its active
metabolite. Therefore, concomitant use of PPIs may
decrease clopidogrel’s effect.49
Clopidogrel resistance has also been linked to gene
polymorphisms.50 Clopidogrel is a prodrug that requires
conversion into active metabolite by hepatic CYP2C19.
The prevalence of poor metabolisers (subjects carrying
two loss-­of-­function alleles) is as high as 58.8% among
Asians.51
PERSPECTIVES
Many challenges remain for the selection of optimal anti-
platelet therapy in the real-­world practice. Currently, we
are still uncertain about the best antiplatelet therapy in
different ethnic populations. For example, is cilostazol
equally effective in blacks or whites as in Asians? We also
need to know the best dose of medications, best combina-
tion and duration of DAPT among patients with diverse
comorbidities, multiple vascular risk factors, high body
mass index, CYP2C19 loss-­of-­function gene mutations or
stroke recurrence while on antiplatelet therapy.
Ticagrelor does not need hepatic activation and was
shown to be more effective than aspirin in patients with

 J, et al. Stroke & Vascular Neurology 2022;7:e001166. doi:10.1136/svn-2021-001166

Shah 411
Open access

Table 3 Current guidelines on the use of antiplatelet therapy for secondary stroke prevention2 10
Noncardioembolic ischaemic
stroke or TIA
Intracranial large artery
atherosclerosis
Extracranial carotid or vertebral Aspirin, clopidogrel or aspirin-­dipyridamole is recommended indefinitely (1/A).10 59
artery stenosis
Extracranial carotid or vertebral In patients with ischaemic stroke or TIA, treatment with antiplatelet or anticoagulation therapy for at least 3
arterial dissection
Aortic arch atherosclerosis
Moyamoya disease
Stroke Vasc Neurol: first published as 10.1136/svn-2021-001166 on 7 April 2022. Downloaded from http://svn.bmj.com/ on August 8, 2023 at Instituto Mexicano del Seguro Social (IMSS).
1. The use of antiplatelet agents is indicated to reduce the risk of recurrent ischaemic stroke and other
cardiovascular events (class 1/Level A).
– Aspirin 50–325 mg daily (1 /A) or aspirin 25 mg/extended-­release dipyridamole 200 mg two times daily
(1/B)
– Clopidogrel 75 mg daily (2 a/B).
2. For patients with minor-­to-­moderate acute noncardioembolic ischaemic stroke or high-­risk TIA, DAPT
(aspirin and clopidogrel or ticagrelor in carriers of CYP2C19 loss-­of-­function alleles) should be started
within 24 hours for 21–30 days, followed by SAPT (1 /A).
3. Long term use of DAPT increases the risk of haemorrhage and is not recommended (3 /A)
4. Triple antiplatelet therapy (aspirin +clopidogrel + aspirin/dipyridamole) for secondary stroke prevention is
harmful and should not be used (III harm/B-­R).
1. In patients with AIS or TIA caused by 50% to 99% stenosis of a major intracranial artery, aspirin 325 mg
daily is recommended in preference to warfarin to reduce the risk of recurrent ischaemic stroke and
vascular death (1/B).56
2. In patients with 70%–99% stenosis of a major intracranial artery, the addition of clopidogrel 75 mg daily to
aspirin for up to 90 days is reasonable (2 a/B).
3. In patients with recent minor stroke or high-­risk TIA and concomitant ipsilateral >30% intracranial
stenosis, the addition of ticagrelor 90 mg two times a day to aspirin for 30 days might be considered to
reduce recurrent stroke risk (2b/B).
4. In patients with stroke or TIA attributable to 50%–99% intracranial stenosis, the addition of cilostazol
200 mg/day to aspirin or clopidogrel might be considered (2b/C).10 57 58
months is indicated to prevent recurrent stroke or TIA (I/ C).60
In patients with an aortic arch atheroma, antiplatelet therapy is recommended to prevent recurrent stroke
(1 /C).10 29 52
The use of aspirin monotherapy may be reasonable for the prevention of ischaemic stroke or TIA (2b/C).

Carotid web
Dolichoectasia
Fibromuscular dysplasia
Antiphospholipid syndrome
Haematologic traits
Embolic stroke of undetermined In patients with ESUS, treatment with ticagrelor or direct oral anticoagulants is not recommended to reduce
source (ESUS)
Atrial fibrillation and CAD
Protected by copyright.
In patients with carotid web in the distribution of ischaemic stroke and TIA, antiplatelet therapy is
recommended to prevent recurrent ischaemic stroke or TIA (1/B)
In patients with vertebrobasilar dolichoectasia, the use of antiplatelet or anticoagulant therapy is reasonable
for the prevention of recurrent ischaemic events (2 a/ C).
In patients with fibromuscular dysplasia (FMD), antiplatelet therapy is recommended for the prevention of
future ischaemic events (1 /C).
In patients with isolated antiphospholipid antibody, antiplatelet therapy is recommended to reduce the risk of
recurrent stroke (1/B).
In patients with prothrombin 20 210A mutation, activated protein C resistance, elevated factor VIII levels or
deficiencies of protein C, protein S or antithrombin III, antiplatelet therapy is reasonable for prevention of
recurrent stroke or TIA (2 a/C)
the risk of stroke (3/B)
The usefulness of adding antiplatelet therapy to anticoagulation therapy is uncertain for reducing the risk of
ischaemic stroke (2b/C).

AF, atrial fibrillation; AIS, acute ischaemic stroke; CAD, coronary artery disease; CAS, carotid artery stenting; CEA, carotid endarterectomy; DAPT,
dual-­antiplatelet therapy.

aortic arch and intracranial atherosclerotic disease.26 37 52
However, in patients with high risk of bleeding, cilostazol
or aspirin-­dipyridamole may be better option.17 21 22
A common clinical practice is increasing the dose of
aspirin or choosing a different antiplatelet agent after a
recurrent TIA or AIS while on aspirin.53 However, system-
atic review and meta-­analysis did not show effectiveness
of increasing the dose of aspirin or changing to another
antiplatelet medication.54
Selecting of appropriate antiplatelet agent should also
be based on compliance, drug tolerance or resistance.
In a systematic review and meta-­analysis, CYP2C19 loss-­
of-­function alleles were found in 25% of white patients
and in 60% of Asian patients.55 Among 15 studies of
4762 patients with stroke or TIA treated with clopido-
grel, carriers of CYP2C19 loss-­ of-­function alleles were
at greater risk of stroke in comparison with noncarriers
(12.0% vs 5.8%; risk ratio, 1.92, 95% CI 1.57 to 2.35;
p<0.001). Therefore, patients with ischaemic stroke or
TIA may need CYP2C19 gene test. In carriers of CYP2C19
loss-­of-­function alleles, ticagrelor is preferred to clopido-
grel for secondary stroke prevention.40
Additional RCTs are warranted to evaluate CYP2C19
gene testing-­based antiplatelet therapy for stroke preven-
tion: (1) Ticagrelor plus aspirin versus clopidogrel plus
aspirin for patients with symptomatic intracranial stenosis
and (2) Ticagrelor plus aspirin vs ticagrelor in patients

412 Shah J, et al. Stroke & Vascular Neurology 2022;7:e001166. doi:10.1136/svn-2021-001166


with symptomatic intracranial stenosis or chronic large
vessel occlusion.
CONCLUSION
SAPT is indicated for secondary stroke prevention in
most patients with noncardioembolic ischaemic stroke
or TIA. DAPT with aspirin and clopidogrel or ticagrelor
for 21–30 days is more effective than SAPT for secondary
stroke prevention when initiated early after minor noncar-
dioembolic stroke or high-­risk TIA. Aspirin is appropriate
and cost-­effective in antiplatelet naïve patients. Cilostazol,
label treatment, would be attractive alternative
as off-­
for patients with high risk for haemorrhage. In patients
with intracranial stenosis, the addition of ticagrelor or
cilostazol to aspirin for up to 30 days might reduce recur-
rent stroke risk. Ticagrelor might be preferred to clopi-
dogrel in patients with CYP2C19 loss of function alleles.
Acknowledgements We appreciate the generous support from the University
of California Irvine Xiaoqi Cheng & Dongmei Liao International Stroke Research
Scholarship.
Contributors JS contributed to drafting and revising the manuscript. SL
contributed to literature review, data collection and revision of the draft. WY
contributed to the conception, intellectual contents, revising the manuscript and
final revision.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests None declared.
Patient consent for publication Not applicable.
Provenance and peer review Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
ORCID iDs
Shimeng Liu http://orcid.org/0000-0002-9659-1778
Wengui Yu http://orcid.org/0000-0003-1664-3580
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